Nature published a commentary by NIH Director Francis S. Collins and NIH Office of Research on Women's Health Director Janine A. Clayton which warns us that the NIH will start insisting on the inclusion of more sex-difference comparisons. These are to extend from cells to animal models across many areas of pre-clinical work.

The NIH is now developing policies that require applicants to report their plans for the balance of male and female cells and animals in preclinical studies in all future applications, unless sex-specific inclusion is unwarranted, based on rigorously defined exceptions. These policies will be rolled out in phases beginning in October 2014, with parallel changes in review activities and requirements.

I cannot wait to see what the "rigorously defined exceptions" will be for several types of research in which I have an interest. Every rat self-admin study must now include both males and females? For all treatment conditions or will it be acceptable to just tack the sex-comparison on at the end?

Furthermore, the NIH will monitor compliance of sex and gender inclusion in preclinical research funded by the agency through data-mining techniques that are currently being developed and implemented. Importantly, because the NIH cannot directly control the publication of sex and gender analyses performed in NIH-funded research, we will continue to partner with publishers to promote the publication of such research results.

oooooh. "partner with publishers" eh? Of course this is because Clayton and Collins realize that higher JIF journals are entirely uninterested in things as pedestrian as sex-comparisons, particularly when the outcome of the study is "no difference". Which, btw, is one of the reasons nobody* wants to waste their precious time and grant money doing something as low-return as sex-comparisons. So somehow the NIH is going to lean on publishers to be...friendlier....to such work. I do hope they realize that this is not going to work. The contingencies are not going to change because the NIH asks. Now, if they actually went all in and dismantled GlamourMagScience culture by the judicious use of grant award, grant auditing and rules about the ratio of publications to effort expended... then we might see some progress. That will never happen and thus there will be no change in the publication contingencies that fight against sex-comparison studies.

Dr. Clayton went on The News Hour where Judy Woodruff asked her (and Phyllis Greenberger of Society for Women's Health Research) some pretty obvious questions. Woodruff wanted to know if there were any clear examples in which women were put at risk or their health suffered because of a lack of such research. She also wanted to know what the implications for research might be- would it be more difficult or more expensive. Finally, Woodruff asked if scientists would resist.

From the transcript:

JUDY WOODRUFF: But how hard is that? Does that mean — is it extra work, is it more expensive? What’s involved in making sure there’s a gender balance?

Now Greenberger snuck in a "Both" off camera but then Clayton went on to be ridiculous and fail to answer the question. The answer is indeed "both" and it is a serious one if the NIH expects to get results. It will be more expensive, progress will be slower and it will be "harder" in the sense of teasing out the right experimental designs and variables so that an interpretable result can be reached. It isn't rocket science, exactly, but it is harder.

JUDY WOODRUFF: Phyllis Greenberger, were there — were there actually individuals who were harmed or where help wasn’t delivered because the research was done only on males?

Greenberger totally walked around this one and Woodruff, to her credit, fronted Clayton with the same question a bit later. Clayton referred to heart attack warning symptoms in women that might differ from men...of course this has nothing whatever to do with preclinical research. Gaaah! So frustrating. Greenberger chimed back in with talk of drugs being removed from the market for adverse effects in women....with no indication that these were adverse effects that would have been identified in female-specific PREclinical research. C'mon NIH! If you are going to take a run at this, please prepare your argument!

JUDY WOODRUFF: And is that the reason that it wasn’t done earlier, Dr. Clayton, that there was just pushback in the scientific community?

The answer is illustrative of the problem at the NIH....

DR. JANINE CLAYTON: It’s hard to say. There are probably a lot of factors that are involved.

And what’s really important now is right now we have been able to put the focus on getting this as a priority. As Phyllis mentioned, the Society and other advocacy groups and scientists and others have talked about this in the past. In fact, we are supporting scientists who are doing this research, but it wasn’t enough of a priority. In some way, it was like a blind spot. Scientists weren’t thinking about it.

Clayton is right. The NIH does indeed support investigators doing sex-differences studies.Those scientists do not have a problem of "priority" from the perspective of their own intrinsic motivation.

With respect to whether scientists resist, I enjoin you to go over to PubMed and type in Sex Differences and see what fill-in choices are offered to you. Click on several of these searches and see what you find. You will find funded projects in many of your favorite domains of interest. If you bother to click on the papers and look at the grant attributions, you may even find that many of these investigations were completed under NIH funding!

So when Clayton (and in the Commentary she is joined by Director Collins) claims it isn't a "priority", it seems misplaced to put this on the shoulders of extramural scientists.

If the NIH wants more sex-differences studies then they need to deploy their tastiest carrot to greater effect. Put out some Funding Opportunity Announcements and see what happens! Fund a few Supplements to the people who are already doing sex-comparisons! Pick up a few grants that missed the payline...again, from the people who are already proposing sex-comparisons!

And if you want to lure in new converts that you didn't get with an RFA or a Program Announcement? This is simple. Just put out a policy that any grant application with a credible stab at a sex-comparison component gets an extra 5 percentile points credit towards the payline for funding.

There is research that aims to uncover, understand, deconstruct and evaluate biological sex differences and their health relevance. The Nature article refers to multiple examples of this type of work, much of which is incredibly important and transformative.

I find it hard to believe that simply requiring sex as a stratifying factor in other research oriented at other biological and behavioral problems enhances that research OR the study of sex differences.

There are many examples in research where we explicitly control a whole range of variables in order to study one, in particular. The one we study may not explain the most variance but it's important: in and of itself. Sex is one example. But there are others, and in those other cases, sex is not the topic of study and shouldn't be forced in.

Yes, sex differences research should be a priority. And you note ways to accomplish that - namely, by rewarding the study of sex differences as its own important discipline.

NIH will monitor compliance of sex and gender inclusion in preclinical research funded by the agency through data-mining techniques that are currently being developed and implemented. The NIH will also work alongside the Central Intelligence Agency (CIA) and the National Security Agency (NSA) to monitor the research activity of scientists all the over the USA. Failure to comply with these new sex-study rules will lead to felony charges, a maximum fine of $250,000/yr for five years, and banishment to a soft-faculty position (if applicable) at a randomly chosen medical school, where the individual will be at the complete mercy of future NIH funding.

I am surprised that there is only one comment on this policy on the Rock Talk Blog. When NIH proposed curtailing the fall review round due to the gov't shutdown, Rockey received many dozens of protests, and they listened and reversed course.

Help me understand this. Are we talking just inclusion of females and makes, or mandatory sex difference studies?

So for example, I have a disease model where I see a difference between control vs. treatment in a given disease parameter, using only males. Based on power analysis and experience, I typically need about 10 controls and 10 treatment, to see statistically significant effects. 20 total.

Now, if all I need is to show that the effect is generalizable across males and females, and include them in the trial (just like an "equal enrollment" mandate in clinical trials, filling the quotas of male, female, different ethnic minorities etc.), I could probably just keep the total numbers the same (5 male + 5 female in control vs. disease). But, because addition of females increases the noise in the system, probably a slightly higher N is required, so let's say 8 males + 8 females per group, 16 control, 16 treatment, 32 total. Overall about a 50% increase in animal numbers! with the result being presented in terms of "treatment is effective, regardless of sex of the animals".

BUT... Such a design would not give adequate power to independently examine the effects of treatment depending on sex. For that I'd need 10 of each sex per group, 40 total, i.e. double the number of mice.

50% more and 100% more are very very different numbers. I have yet to see clarification on whether NIH is merely looking for inclusion, or is specifically asking researchers to reformulate their hypotheses to present results in which sex is an independent factor that must be controlled for, with break-down of all data on the basis of sex. It's clearly a very important distinction, for which some leadership would be good right now - for example, those of us with long running animal models where having to do something different in October (5 months from now) is kinda short notice!

Adding to the expense issue for mouse studies, males kept all together in rooms with only males will not fight so much, compared to when females are present. Doing everything in males and females (versus males only) will mean more mouse rooms for vivariums. I would love to hear AAALAC's take on this - how can a vivarium simply simply double in size overnight? If males and females are kept in the same rooms males will fight more and animal suffering will increase. Veterinary bills will skyrocket due to numbers of males being tagged on vet rounds for fight lesions, and having to be moved to 1 male per cage status, further increasing per diem costs.

Help me understand this. Are we talking just inclusion of females and makes, or mandatory sex difference studies?

It seems pretty clear to me that this has not been fully considered and the specific policies vis a vis "rigorously defined exceptions" are in development. I would suggest that people help the NIH to generate these policies by discussing the implications and your suggested definitions loudly and repeatedly. Including at....

I am surprised that there is only one comment on this policy on the Rock Talk Blog.

As I read this, the key term is "preclinical", which traditionally refers specifically to drug discovery research in cells and animals. This is distinct from translational and basic research, which in this nomenclature would be "pre-preclinical".

Assuming NIH clarifies that this is what they mean, I don't think C. elegans douches or crystallographers or other basic and translational researchers are involved in this.

Preclinical = basic, as far as I understand the usage. Plus watch the interview- they explicitly pushing the cell line gender stuff (hello HeLa cells). The inmates have assumed control of the asylum. I despair. Research funding is zero sum game and the set asides for nonsense politically motivated work are adding up, so I vehemently disagree with DM suggestion of a +5% carrot. Inclusion of females and minorities in clinical studies is reasonable. This, on high, diktak from some half-baked affirmative action gender hire at NIH is just out and out ridiculous.

I think you will be sorely disappointed if you think any aspect of basic research will be automatically excepted. Now, over the coming months and years there may be entire models that enjoy a "rigorously defined exception" but this will have to be spelled out.

Much like I think it is horrible that the NIH people being put in front of cameras don't have a ready answer to obvious questions, I think it will be stupid if basic researchers don't come up with a good answer for their "rigorously defined exception" to doing sex-comparisons.

For instance, "male worms are one in a thousand" seems like a half decent soundbite to me.

Totally awesome thinly veiled misogyny in the comments. Keep up the good work, boys.

A good example of a drug where not understanding the basic mechanisms in females has lead to human problems are statins. Rates of tendon rupture in women on statins far exceed males. Statins have also not been shown to help the risk of heart disease in post menopausal women without additional disease (eg type 2 diabetes) and in fact, seem to increase the risk of type 2 diabetes...but I can see NIH officials being hesitant to burn the most widely prescribed drugs in the country, which would heretofore be classified as an NIH "success".

You all remind me of the migraine researchers I've met who do all their work on male animals. Given not only the heavy female bias of migraine rates, but the strong association between ovarian hormone status and migraine frequency, the bullshit blind spot about females being "too variable" would seem to have been in effect, and as a female migraine sufferer I eagerly await the bullshit mechanisms these guys will dream up about meningital pain that have nothing to do with the pathophysiology in the majority of the suffering population.

In conclusion, U Mad Bro? now you people have to start considering whether your bullshit is sex universal, or actually shows an interesting sex difference. See? You win either way! But short sightedness, and yes, I will suggest deep misogyny again, are making you throw tantrums.

Ahem, there you go.. Knuckle under or your a pig. Look schrew, I think the examples you cite are reasonable avenues to investigate. Knock yourself out. What rankles is the mandate for everybody to look at gender differences- one size fits all. Plus the cell line shtick just strikes me as bizarre.

Its arguable, and I could well be wrong, but judging from the interview on PBS Dr. Clanton is a political creature that has little idea about how basic research is conducted and what motivates its practitioners. I mean, come on, we are not a bunch of southern small town sheriffs.

Honestly, I think this initiative will go by the wayside. The interview on News Hour was the goal. Look gals, we care about you and we are bringing these sexist scientists with their blind spots and subtle prejudices to heel. We will order them to study gender; and work with the publishers to ensure that they do. Animal Farm, academic freedom? anyone anyone?

Schrew, I want you to remember this exchange when you are a lab head and working in academia or government down the road. A moment might come when you realize that a goodly portion of your time is consumed by trivial hoop-jumping nonsense. I would ask that you allow a fleeting thought that maybe ol reactionary Sid had a point. peace

Wow! What a great trip! Thanks for the time travel, dudebros! It was fun going back to visit the attitudes of yesteryear. Half-baked affirmative action gender hire! Mandates that rankle! Political creatures who don't understand basic research! It would be good to look at sex differences, just, you know, not all the time! Only when it matters! And pay me extra for the bother! Because normal science is about one gender!

Now that we are back here in 2014: I eagerly await an answer to AsianQuaterBack's question. It will be so cool to see if you guys can figure it out.

Or, you know, just keep working on those creative methods to get your exemptions because Everyone Knows That Males Are The Norm And Females Are A Messy Mystery That Will Wreak Havoc On Our Beautiful Orderly Science. It simply cannot be done. Not no how, not no way.

Oh, if only there were a bunch of brilliant minds that could be brought to bear on solving this problem. Alas!

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